Common complications of portal hypertension include gastroesophageal varices, ascites, and portasystemic encephalopathy. Patients with cirrhosis have a 5-10% yearly incidence of variceal formation, and a 4-15% yearly incidence of bleeding. Each bleeding episode carries up to a 20% risk of death. Consequently, the development of an accurate and noninvasive technique for measurement of portal venous pressure would represent a major advance in the diagnosis and management of portal hypertension. Currently, clinicians evaluate portal hypertension through the hepatic venous pressure gradient (HVPG) determined by the gradient in pressure readings between wedged and free hepatic vein catheter positions via a transjugular approach. Our group has proposed an innovative ultrasound technique called subharmonic-aided pressure estimation (SHAPE) for noninvasive pressure measurements and produced the first ever in vivo SHAPE estimates (in canines). Recently, we conducted a first-in-humans, pilot study of this technique's ability to estimate portal pressures i 45 patients undergoing transjugular liver biopsy supported by an NIDDK Challenge Grant (RC1 DK087365). The SHAPE gradient between the portal and hepatic veins was in good agreement with the corresponding HVPG (R = 0.82). More importantly, subjects with portal hypertension (HVPG > 10 mmHg) showed significantly higher subharmonic gradients than those with lower HVPGs (p < 0.001). Given these encouraging results, this application brings together researchers and clinicians from Thomas Jefferson University (TJU) as well as the Hospital of the University of Pennsylvania (HUP) with a premier manufacturer of ultrasound scanners (GE Healthcare) in order to produce a device for noninvasive and accurate assessment of portal hypertension. The SHAPE algorithm will be optimized by pulse shaping and implemented on a state-of- the-art ultrasound scanner (Logiq 9, GE Healthcare, Milwaukee, WI) for real time pressure measurements. Following calibration studies in the hepatic and portal veins of 3 canines, we will conduct a large scale clinical trial of the novel implementation of SHAPE in 300 patients undergoing a transjugular liver biopsy at TJU or HUP (using HVPG as the reference). We will also monitor disease progression or treatment response in patients identified with portal hypertension by comparing SHAPE results to repeat biopsies and/or clinical outcomes. Hence, this study aims to further develop a novel and innovative ultrasound based technology (i.e., SHAPE) for the noninvasive evaluation of portal hypertension and to conduct a large scale human clinical trial to conclusively establish the accuracy of SHAPE for the assessment of portal hypertension.